The present invention relates to a method and composition for treating reperfusion injury.
Ischemia refers to a condition wherein tissue suffers from a decrease or cessation of perfusion by blood. Ischemia can occur due to a blockage of the blood vessels, for example, due to atherosclerosis, heart attack, stroke, during organ transplant, or tissue necrosis as might be seen in liver disease.
Cardiac tissue is susceptible to ischemia and can be severely damaged by such an event. Accordingly, recovery from cardiac ischemia is critical in order to ensure proper cardiac function, which is related to survival of the patient. A cardiac ischemic event can be caused, for example, by heart attack or other disease states or from therapeutic intervention such as angioplasty or bypass surgery.
Although, a goal is to terminate an ischemic event, and to reestablish normal blood flow to the cells, the resultant reperfusion can result in a reperfusion injury damaging cells. A number of mechanisms have been proposed to explain reperfusion injury including: 1) cell swelling due to sodium and water influx; 2) calcium influx with resultant contraction bands and formation of calcium phosphate granules or crystals within mitochondria; 3) hemorrhage, secondary to vascular and/or microvascular injury; and 4) generation of a biologically significant quantity of oxygen free radicals. See, Flaherty, et al., Reperfusion Injury, Free Radical Biology & Medicine, Volume 5, pages 409-419, 1988.
Free radicals are molecules with an unpaired electron creating an unstable and highly reactive molecule. Oxygen free radicals are highly reactive with biological macromolecules such as are found in cell membranes, and thereby can induce cell damage.
Oxygen induced cell damage can occur in ischemic myocardium, as a result of reperfusion. A number of dysfunctions, which impair cardiac recovery after ischemia, have been shown to be associated with reperfusion, including: reperfusion arrhythmias; stunned myocardium; the "oxygen paradox"; and the development of infarction. See, Darley-Usmar, et al., Oxygen and Reperfusion Damage: An Overview, Free Rad. Res. Comms., Volume 7, No. 3-6 (1989).
There is increasing evidence that oxygen free radicals play a major role in the pathogenesis of reperfusion injury. See, Darly-Usmar and Flaherty, supra. The production of lipid peroxides and other active oxygen radicals during reperfusion are believed to result in tissue necrosis or damage.
Another focus of clinically significant ischemic/reperfusion injury is the intestines. This can occur in two principal ways. The first is caused by a hypoxic insult to the patient, for example in newborn infants who undergo difficult deliveries, or who are inadequately warmed just after delivery. In such patients and conditions it is believed that brief or prolonged periods of hypoxia can lead to intestinal ischemia. This, and subsequent reperfusion, can lead to a condition known as necrotizing enterocolitis (NEC), wherein the intestine in effect necroses, or rots, and must be partly or totally removed by surgical means.
Similarly, ischemia can be experienced by the intestine as when a blood clot, formed elsewhere in the body, travels and lodges in a major artery of the intestine. This thereby limits blood flow to the intestine. Resolution, or passing, of the clots can yield a reperfusion period and tissue damage.
Another example of ischemic/reperfusion injury is subsequent to cerebral blood clot and infarct. Cessation of blood flow damages adjacent tissue. Reperfusion, following administration of thrombolytics, can expand the size of the necrotic brain tissue.
Additional ischemic injuries may also occur in patients who are being prepared for artificial blood substitutes, either fluorocarbons or chemically modified hemoglobin. These patients are ischemic then exposed to high levels of oxygen provided by the blood substitute.
In all of the above conditions, the ischemic event and subsequent reperfusion are associated with damage to the organ, which can range in severity from minimal to fatal.